Abstract

The presence of activating BRAF mutations in approximately 50% of melanomas, the majority of which are BRAFV600E, has prompted the development of selective inhibitors of the BRAF/MAPK/ERK pathway for targeted therapy. RAF inhibitors, including vemurafenib and GSK2118436, have shown striking results in clinical trials, highlighting this pathway as a suitable target for melanoma therapy. A number of other pharmacological agents targeting this pathway are currently in pre-clinical or clinical development. However, therapy with MAPK pathway inhibitors results in a wide range of response patterns in patients with BRAF-mutant tumors. Furthermore, even in patients with measurable responses, tumors eventually develop resistance and patients relapse. It has been previously reported that activation of the PI3K pathway may play a role modulating the response to RAF and MEK inhibitors. Here we report that melanoma cells which harbor the BRAFV600E mutation and express PTEN have low levels of phospho-AKT and are sensitive to a novel ATP-competitive ERK inhibitor. In contrast, BRAFV600E mutant melanoma cell lines that do not express PTEN have higher levels of phospho-AKT and are less sensitive to ERK inhibition. Importantly, we have confirmed these findings in an in vivo xenotransplantation model of melanoma. Additionally, we found that siRNA-mediated PTEN silencing in a PTEN wild-type cell line modestly decreases sensitivity to ERK inhibition. Conversely, PTEN overexpression in a PTEN-null cell line partially sensitizes cells to the ERK small molecule inhibitor. Consistent with these findings, targeting PI3K in melanoma cells lacking functional PTEN sensitizes them to ERK inhibition. Our studies suggest that the presence or absence of functional PTEN can modulate response to ERK inhibitors and warrant further evaluation of combination strategies to treat melanomas refractory to inhibitors of the MAPK pathway.